1. Field of the Invention
This invention relates to methods of preparing cationic complexes of Tc-99m which are useful as myocardial imaging agents and to novel compositions containing Technetium-99m complexes.
2. Prior Art
Diagnostic nuclear medicine involves the administration to a subject of a radiation-emitting isotope which localizes in the tissues of interest. An image of these tissues is then obtained using a scintillation camera such as an Anger scintillation camera. Tc-99m is an ideal radioisotope for use in nuclear medicine. It has a half-life of 6 hours and a gamma-radiation of 140 keV, with no alpha or beta radiation. It is easily prepared using a Mo-99/Tc-99m generator and it is relatively inexpensive. Finally, its chemistry is such that it can be incorporated into diverse chemical forms in order to image different types of tissues.
Tc-99m has become widely used for scintillation scanning of bone tissue and infarcted myocardial tissue. In these applications, the Tc-99m is administered with a carrier such as methanehydroxydiphosphonate and a reducing agent such as SnCl.sub.2. The Tc-99m-diphosphonate complex acts as a calcium-seeking agent which accumulates in bone, particularly at sites of high calcium turnover in newly forming or cancerous bone, and in myocardial infarcts that contain calcium phosphate.
Within the past several years, interest has developed in producing Tc-99m-based radiodiagnostic agents which will accumulate in normal heart tissue, as opposed to infarcted tissue. Such radiodiagnostic agents would be of great benefit inasmuch as they would allow for the early identification of individuals at high risk of having heart attacks. Deutsch and coworkers determined that the cationic Tc-99m complex [.sup.99m Tc(dmpe).sub.2 Cl.sub.2 ].sup.+, where dmpe is bis(1,2-dimethylphosphino)ethane, accumulated in normal dog heart tissue, allowing gamma-ray images to be taken (Science, 214:85-86 [1981]).
Several additional Tc-99m cationic complexes have been described of interest for studies dealing with the imaging of normal heart tissue. Most prominent have been [.sup.99m Tc(dmpe).sub.3 ].sup.+, Gerson, M. C., Deutsch, E. A., et al., Eur. J. Nuc. Med., 9:403 [1984] and [.sup.99m Tc(tBuNC).sub.6 ].sup.+, Jones, A. G., et al., Int. J. Nucl. Med. Biol., 11:225 [1984]; Jones, A. G., Davidson, A., Abrams, A. J., U.S. Pat. No. 4,452,774. Clinical imaging with these agents is less than optimal. Therefore, a need still exists for additional Tc-99m complexes which will accumulate preferentially in heart tissue.
Technetium-arene complexes have received only cursory attention in the literature, usually being prepared for comparative studies with analogous manganese or rhenium compounds. The preparations of cyclopentadienyl and benzene derivatives were reported as early as 1961 (Huggins, D. K. and Kaesz, H. D., J. Amer. Chem. Soc., 83:4474 [1961]; Fischer, E. O. and Schmidt, M. W., Chem. Ber., 100:3782 [1967]; Baumgartner, F. et al., Chem. Ber., 94:2198 [1961]; Palm, C. et al., Tet. Lett., 1962(6) 253). Preparation of a hexamethylbenzene derivative was described by Fischer, E. O. and Schmidt, M. W., Chem. Ber., 102:1954 (1969). Since that time the compounds have received no further attention in the literature.
The benzene and hexamethylbenzene complexes are sandwich-type compounds in which a technetium(I) atom is II-bonded to two arenes, giving a cationic complex. Synthetic routes to the benzene and hexamethylbenzene complexes of Tc-99, as reported in the prior art, are long and involved, making them unacceptable for commercial use. The prior art procedures generally use TcCl.sub.4 as the starting material, a substance which is not easily prepared from the NaTcO.sub.4 obtained from Mo-99/Tc-99m generators. In the prior art procedures, TcCl.sub.4 and benzene or hexamethylbenzene (along with other reagents) are heated in a sealed tube for 3 days or 24 hours, respectively. Since the half-life of Tc-99m is 6 hours, it is apparent that most of the Tc-99m obtained from a generator will have decayed into non-radioactive Tc-99 in the time required to prepare a technetium-arene complex by the prior art processes. Accordingly, it is not possible to prepare Tc-99m-arene complexes having desirably high ratios of Tc-99m/Tc-99 which are practically useful as radiodiagnostics using the procedures of the prior art.